HIV-1-specific T cell responses have strong antiviral activities and are therefore of particular interest for HIV-1 vaccine design. However, a deep understanding of immunoregulatory mechanisms that determine their evolution and function will be critical for their in vivo manipulation by vaccines and immunogens. Here, the PI proposes an entirely novel, previously unrecognized mechanism for the regulation of HIV-1 specific T cells through activating or inhibitory myelomonocytic MHC class I receptors on dendritic cells and monocytes. In her preliminary studies, the PI has found that HIV-1 CTL epitope/MHC class I complexes bind to these receptors in an antigenic peptide-specific fashion, thus suggesting an HIV-1 sequence- specific mechanism for the functional regulation of dendritic cells. Strikingly, the PI observed that HIV-1 CTL escape mutations can critically enhance the binding intensity of HIV-1 CTL epitope/ MHC class I complexes to inhibitory myelomonocytic MHC class I receptors and thus lead to a tolerogenic functional profile of dendritic cells, suggesting a connection between CTL epitope escape, altered recognition by myelomonocytic MHC class I receptors and functional changes of myelomonocytic cells. Based on these observations, the PI proposes to comprehensively assess binding properties of HIV-1 CTL epitope/MHC class I complexes to activating or inhibitory myelomonocytic receptors, how these interactions are affected by HIV-1 sequence evolution, and in which way these mechanisms result in functional alterations of dendritic cells and HIV-1- specific T cells. Moreover, the PI will test if associations between HLA class I alleles and HIV-1 disease progression correlate with specific patterns of recognition of these alleles by activating or inhibitory myelomonocytic receptors. Overall, these investigations open an entirely new perspective for the assessment of how HIV-1 can manipulate dendritic cells and ensuing HIV-1-specific T cells in a viral sequence-specific pattern by binding to myelomonocytic receptors and will thus be critical for HIV-1 vaccine design. PUBLIC HEALTH RELEVANCE: Dendritic cells can determine the functional profile of HIV-1-specific immune responses, and therefore are critical for HIV-1 vaccine design. In the proposed studies, the PI will analyze how HIV-1 viral sequence evolution can affect the functional activity of dendritic cells through interactions with myelomonocytic receptors. These investigations will be crucial for identifying correlates of protective immunity against HIV-1, and ultimately developing effective HIV-1 vaccines.